The present invention relates to a novel crystal of a highly sweet substance (sweetener) of N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl]-L-phenylalanine methyl ester with improved dissolution rate (solubility), a process for producing the same, and a granule of said crystal excellent in dissolution rate. For reference""s sake, as is well-known, L-xcex1-aspartyl-L-phenylalanine methyl ester is a kind of amino acid-based highly sweet sweetener whose commercialization has already been established, and it is abbreviated to xe2x80x9cAPMxe2x80x9d or xe2x80x9cAspartamexe2x80x9d. Accordingly, the above described sweet substance according to the present invention can be regarded as a derivative of APM or Aspartame, and therefore is abbreviated hereinafter to xe2x80x9cN-(3,3-dimethylbutyl)-APMxe2x80x9d. This sweet substance may be abbreviated to xe2x80x9cNMxe2x80x9d (xe2x80x9cNeotamexe2x80x9d) in some literatures.
The efficacy of sweetness of N-(3,3-dimethylbutyl)-APM is at least 50 times as high as that of Aspartame in weight ratio and is about 10,000 times as high as that of sucrose (table sugar), and thus it can constitute a very strong sweetening agent (sweetener).
Because sweeteners are mainly intended for use in foods and consumed by persons, they should be prepared by processes enabling preparing high-purity preparations substantially free from impurities and decomposed materials. To be usable in an industrial scale, such processes should have been established so as to be reproducible at relatively low costs.
The crystal structure of already known N-(3,3-dimethylbutyl)-APM is described as IR spectrum data in WO95/30689. Further, the present inventors analyzed the structure of its single crystal, and as a result, they confirmed that this crystal is a monohydrate, and when measured by powder X-ray diffractometry, the crystal shows characteristic peaks in diffractive X-ray (X-ray diffraction pattern) at diffraction angles (angles of diffraction) at least 6.0xc2x0, 24.8xc2x0, 8.2xc2x0, and 16.5xc2x0 (2xcex8, CuKxcex1 ray (radiation; line)). For the sake of convenience, the present inventors referred to this crystal as xe2x80x9cA-type crystalxe2x80x9d.
However, the dissolution rate of the A-type crystal in water is low, so there is a commercial and industrial problem in view of the product qualities.
Under the background of such prior art techniques, the problem to be solved by the invention (the object of the present invention) is to provide a novel crystal of a highly sweet sweetener N-(3,3-dimethylbutyl)-APM with improved dissolution rate (solubility), a process for producing the same, and granules of said crystal, improved in solubility.
As a result of their eager study to solve the above-described problem, the present inventors have found that the water content of dry A-type crystal is usually 3 to 6% (inclusive of water of crystallization), but if this A-type crystal is further dried until its water content is reduced to less than 3%, a novel crystal of N-(3,3-dimethylbutyl)-APM with improved dissolution rate (solubility), from which water of crystallization has been eliminated, is obtained, and also that this novel crystal is granulated (converted into the granules form) whereby its dissolution rate is further improved, and on the basis of these findings, the present invention has been completed. For reference""s sake, this novel crystal was referred to as xe2x80x9cC-type crystalxe2x80x9d.
That is, the present invention relates to a novel crystal (C-type crystal) of N-(3,3-dimethylbutyl)-APM, which when measured by powder X-ray diffractometry using CuKxcex1 ray (line), shows characteristic peaks in diffractive X-ray at diffraction angles different from those of the A-type crystal, that is, at diffraction angles (2xcex8) of at least 7.1xc2x0, 19.8xc2x0, 17.3xc2x0, and 17.7xc2x0, as well as a process for producing the same, and granules of said novel crystal.
The C-type crystals of the present invention can be obtained for example by drying the A-type crystals until their water content is reduced to less than 3% by weight, as described above.
Many kinds of processes, such as various synthesis processes (methods) are known for the process for producing N-(3,3-dimethylbutyl)-APM, but as a matter of course, the crystal of the present invention can be obtained by not depending on the processes for producing N-(3,3-dimethylbutyl)-APM itself or the kinds thereof.
A dryer (drying equipment) for drying the A-type crystals to obtain the C-type crystals is not limited particularly. Although a through-flow dryer, a fluidized bed dryer, a vacuum dryer, a spray-dryer, a micron dryer, and etc. can be used widely, a vacuum dryer is preferably used.
The production of granules from the C-type crystals as the novel crystals of N-(3,3-dimethylbutyl)-APM made by the present inventors is not particularly limited, and any known and conventionally used granulation process in this field can be suitably used and applied therefor. For example, a dry granulation process or a wet granulation process may be used. Specifically, any method such as mixing granulation, roll press granulation, extrusion granulation, fluidized bed granulation, tumbling granulation, pulverizing granulation, spray-coating, tabletting, and etc. can be used, but the dry granulation method, such as roll press granulation is industrially advantageous for low thermal loading and for easy operation processes without complicated tasks.
For the purpose of easy applications or improvement in quality of sweetness, depending the use applications, the granules of N-(3,3-dimethylbutyl)-APM of the present invention, similar to conventional highly sweet sweetener compositions, can incorporate diluents (thinners) and excipients, such as sugar alcohols, oligosaccharides, food fibers (dietary fibers) and the like, or other highly sweet synthetic sweeteners, such as Alitame, saccharin, and etc., in an amount within such a range as not to spoil the dissolution rate improved by the present invention. The diluents and excipients in this case include sweeteners having a low degree of sweetness, such as sucrose and glucose.
Granulation for a predetermined range of particle diameter can be effected in any method known in the art by subjecting the produced granules to screening and the like.
N-(3,3-dimethylbutyl)-APM is converted into granules having a particle size (diameter) in the range of 100 to 1,400 xcexcm, preferably 100 to 500 xcexcm whereby its dissolution rate (solubility) is further improved, rather than the raw powder form thereof, as is evident, for example, from Test Example 2 below. If the particle size is less than the above range, an action to prevent or suppress (depress) the formation of agglomerates becomes weaker, while with a particle diameter exceeding the above range, its specific surface area becomes smaller, and therefore, the effect of improving dissolution rate is lowered in both the cases.